Aging-related Traits and Disease Risk Factors in a Sardinian Population Cohort

SardiNIA研究人群队列包括来自撒丁岛四个城镇的7，000多名受试者，年龄从14-102岁开始。该研究已经测量了超过600个数量性状（内在表型或定量风险相关的遗传或环境因素），可以在连续量表上进行评分，并被设计为纵向研究，在其任期的前15年内进行了4次访问。特别感兴趣的特征包括一系列心血管危险因素，人体测量，血液测试值和个性方面。研究队列的第四次访视已经完成，以便更深入地评估纵向趋势和结局，以及评估与骨密度和脆弱性相关的其他表型作为年龄的函数。例如，24小时血压测量和超声心动图正在扩展对心血管特征的分析;听力测试和视网膜图正在将研究扩展到衰老中的感觉缺陷;该队列已特别扩展到超过250名92岁以上的人，以分析极端年龄的影响。 通过这一队列，已经确定了各种流行病学和遗传因素，包括最近的流行病学研究，这些研究涉及与白色被毛或隐性高血压、昼夜血压模式或尿酸水平相关的人格特征;慢性肾脏疾病和未知甲状腺疾病的患病率;以及动脉硬化和代谢综合征的影响。全基因组DNA测序和基因分型专用芯片（代谢芯片，免疫芯片和外显子组芯片，以及设计用于在整个基因组中提供相等覆盖的芯片）。还分析了整个队列，以产生遗传变异数据，其等位基因频率低至0.1%，23，107，086个单核苷酸多态性（SNP）和3，053，323个插入/缺失（indels），可用于分析性状和自身免疫性疾病中的遗传因素。 GWAS指出，基因/变异决定了每种性状和疾病变异的遗传贡献的重要部分。与其他人群队列的联盟努力相结合，包括巴尔的摩老龄化纵向研究和由NIA支持的InCHIANTI研究，越来越多的出版物鉴定了与肥胖、心血管特征、血脂和血液成分水平相关的基因。 GWAS联盟的研究也推进了技术方法，包括定量血压性状平均值的有用性;质量控制;变异的综合注释;以及使用等位基因评分挖掘人类表型组。至于与性状和疾病有关的遗传因素的GWAS，去年联盟的努力已经发现了与吸烟影响的肥胖和血浆渗透压相关的变异。 在一项新的倡议中，我们正在深化对感觉能力的分析，完成对听力测试的分析，并正在进行视网膜照片中微血管的研究。 这些具有详细的年龄相关变化，通常与疾病表型相关。 近年来，GWAS的研究结果在三篇Nature Genetics论文中报道了几个特征： 两个新的基因变异被发现对撒丁岛人的身高有显着影响。它们加在一起似乎可以使身高降低6厘米。 脂质和炎症--我们确定了14种与血脂水平相关的新的遗传变异，以及19种与血液中的炎症标志物相关的遗传变异。血脂水平和炎症标志物都会影响心脏病的风险。 研究人员第一次同时分析了A1、A2和胎儿血红蛋白水平的基因调控，看看它们的调控是否有任何协调。在10个位点发现了23个关联，包括5个新的候选基因。一半的变异与一种以上的血红蛋白有关。 一种辅助方法，撒丁岛患者和对照组的队列被组装并对几种疾病中的每一种进行GWAS基因分型，1型糖尿病，多发性硬化症（MS）和乳腺癌。这使得我们在《新英格兰医学杂志》上的报告成为MS风险的一个重要因素。在一项正在进行的研究中，我们用流式细胞仪表征了辅助性T细胞和细胞毒性T细胞、调节性T细胞、B细胞、单核细胞和树突细胞的细胞比率和细胞表面标志物的表达--以中值荧光强度（MFI）进行评估，从而在3,757名SardiNIA个体中获得了730种定量免疫细胞特征。将上面提到的定量免疫细胞性状与我们的超密集遗传图谱相关联，总共产生了67个与自身免疫相关的相关基因座。（手稿正在编写中）。 我们已经将研究扩展到相关指标的范围，包括已发表的关于C反应蛋白单核细胞趋化蛋白-1（MCP-1）、白细胞介素-6（IL-6）、脂联素和可溶性BAFF的数据。 此外，我们使用浊度法和Luminex测定法测量了来自同一队列的个体中主要免疫球蛋白类型（IgM，IgG和伊加）的循环水平，并发现了18种全基因组关联。

The SardiNIA study population cohort comprises over 7,000 subjects, starting at ages from 14-102, from a cluster of four towns in Sardinia. The study has been measuring >600 quantitative traits (endophenotypes or quantitative risk-related genetic or environmental factors) that can be scored on a continuous scale, and is designed as a longitudinal studies, with 4 visits over the first 15 years of its tenure. Traits of special interest include a range of cardiovascular risk factors, anthropometric measurements, blood test values, and facets of personality. Fourth visits have been completed for the study cohort to permit more incisive assessment of longitudinal trends and outcomes, as well as the assessment of additional phenotypes related to bone density and frailty as a function of age. For example, 24 hour blood pressure measurements and ECHOcardiography are extending the analysis of cardiovascular traits; hearing tests and retinograms are extending studies to sensory deficits in aging; and the cohort has been specifically extended to over 250 individuals over 92 years of age to analyze effects of extreme age. With this cohort, a variety of epidemiological and genetic factors have been identified, including recent epidemiological studies have been done of personality traits associated with white coat or masked hypertension, with circadian blood pressure patterns, or with uric acid levels; of the prevalence of chronic kidney disease and unknown thyroid disorders; and of arterial stiffness and influences of the metabolic syndrome. Full-genome DNA sequencing and genotyping with specialized chips (metabochip, immunochip, and exome chip, and a chip designed to give equal coverage across the entire genome). The whole cohort has also been analyzed to yield genetic variation data down to allelic frequencies of 0.1% 23,107,086 single nucleotide polymorphisms (SNP) and 3,053,323 insertions/deletions (indels) available for the analysis of genetic factors in traits and autoimmune diseases. GWAS pointed to genes/variants that determine a significant portion of the genetic contribution to variance for each trait and disease. In conjunction with consortium efforts on other population cohorts, including the Baltimore Longitudinal Study of Aging and the InCHIANTI study supported by the NIA, an increasing number of publications have resulted that identify genes associated with obesity, cardiovascular traits, and levels of lipids and blood components. GWAS consortium studies have also advanced technical approaches, including the usefulness of averaging of quantitative blood pressure traits; quality control; integrative annotation of variants; and mining the human phenome using allelic scores. As for GWAS of genetic factors involved in traits and diseases, Consortium efforts in the last year have discovered variants associated with obesity affected by smoking, and with plasma osmolality. In a new initiative, we are deepening the analysis of sensory capacity, with completed analyses of hearing tests and ongoing studies of microvasculature in retinal photographs. Those have detailed age-related changes that often correlate with disease phenotypes. In recent years, GWAS findings have been reported for several traits in three Nature Genetics papers: Two new gene variants were found to have a significant effect on stature in Sardinians. Together, they appear to reduce height by 6 centimeters. Lipids and Inflammation -- We identified 14 novel genetic variants associated with serum lipid levels, as well as 19 associated with inflammatory markers in the blood. Both lipid levels and inflammatory markers influence risk of heart disease. For the first time, researchers concurrently analyzed gene regulation of A1, A2 and fetal hemoglobin levels, to see if there was any coordination in their regulation. Twenty-three associations were seen at 10 loci, including five new gene candidates. Half the variants showed associations with more than one type of hemoglobin. An auxiliary approach, cohorts of Sardinian patients and controls were assembled and genotyped for GWAS for each of several diseases, Type 1 diabetes, multiple sclerosis (MS), and breast cancer. This has permitted our report in the New England Journal of Medicine an important factor in MS risk. In an ongoing initiative we FACS characterized cell ratios and expression of cell surface markers -- assessed as median fluorescence intensity (MFI) -- of helper T cell and cytotoxic T cells, regulatory T cells, B cells, monocyte cells, and dendritic cells, resulting in 730 quantitative immune cell traits in 3,757 SardiNIA individuals. Correlating the quantitative immune cell traits mentioned above with our ultra-dense genetic map yielded a total of 67 associated loci correlated with autoimmunity. (manuscript in preparation). We have extended the studies to range of related measures, including published data on C-reactive protein monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), adiponectin, and soluble BAFF. Furthermore, we have measured the circulating levels of the main immunoglobulin types (IgM, IgG and IgA) using both turbidimetric and Luminex assays in individuals from the same cohort, and saw 18 genome-wide associations.